title: Liposome-encapsulated dexamethasone attenuates ventilator-induced lung inflammation.
abstract: OBJECTIVE
  Systemic glucocorticoid therapy may effectively attenuate lung inflammation but also induce severe side-effects. Delivery of glucocorticoids by liposomes could therefore be beneficial. We investigated if liposome-encapsulated dexamethasone inhibited ventilator-induced lung inflammation. Furthermore, we evaluated whether targeting of cellular Fcγ-receptors (FcγRs) by conjugating immunoglobulin G (IgG) to liposomes, would improve the efficacy of dexamethasone-liposomes in attenuating granulocyte infiltration, one of the hallmarks of lung inflammation.
  
  
  METHODS
  Mice were anaesthetized, tracheotomized and mechanically ventilated for 5 h with either 'low' tidal volumes ∼7.5 mL·kg(-1) (LV(T) ) or 'high' tidal volumes ∼15 mL·kg(-1) (HV(T) ). At initiation of ventilation, we intravenously administered dexamethasone encapsulated in liposomes (Dex-liposomes), dexamethasone encapsulated in IgG-modified liposomes (IgG-Dex-liposomes) or free dexamethasone. Non-ventilated mice served as controls.
  
  
  RESULTS
  Dex-liposomes attenuated granulocyte infiltration and IL-6 mRNA expression after LV(T) -ventilation, but not after HV(T) -ventilation. Dex-liposomes also down-regulated mRNA expression of IL-1β and KC, but not of CCL2 (MCP-1) in lungs of LV(T) and HV(T) -ventilated mice. Importantly, IgG-Dex-liposomes inhibited granulocyte influx caused by either LV(T) or HV(T) -ventilation. IgG-Dex-liposomes diminished IL-1β and KC mRNA expression in both ventilation groups, and IL-6 and CCL2 mRNA expression in the LV(T) -ventilated group. Free dexamethasone prevented granulocyte influx and inflammatory mediator expression induced by LV(T) or HV(T) -ventilation.
  
  
  CONCLUSIONS
  FcγR-targeted IgG-Dex-liposomes are pharmacologically more effective than Dex-liposomes particularly in inhibiting pulmonary granulocyte infiltration. IgG-Dex-liposomes inhibited most parameters of ventilator-induced lung inflammation as effectively as free dexamethasone, with the advantage that liposome-encapsulated dexamethasone will be released locally in the lung thereby preventing systemic side-effects.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, Utrecht, the Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Hegeman
authors.forename: P M
authors.initials: PM
authors.lastname: Cobelens
authors.forename: Jaam
authors.initials: J
authors.lastname: Kamps
authors.forename: M P
authors.initials: MP
authors.lastname: Hennus
authors.forename: N J G
authors.initials: NJ
authors.lastname: Jansen
authors.forename: M J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: A J
authors.initials: AJ
authors.lastname: van Vught
authors.forename: G
authors.initials: G
authors.lastname: Molema
authors.forename: C J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D007074:Immunoglobulin G / Q000737:chemistry; D008081:Liposomes; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000893:Anti-Inflammatory Agents; D007074:Immunoglobulin G; D008081:Liposomes; D017452:Receptors, IgG; D003907:Dexamethasone